In 1954 Vague identified central adiposity as a key determinant of several common chronic diseases including diabetes, myocardial infarction, hypertension and stroke. Vague contrasted the 'apple' pattern with metabolically beneficial gluteal - femoral adipose tissue (pears). This observation spawned more than a half century of clinical and laboratory investigation yet, there is still a major gap in our knowledge regarding th molecular underpinnings of adipose tissue patterning. It is clear that the relationship between adiposity and cardiovascular and diabetes disease risk is tightly related to fat patterning (apple vs. pear). In this regard, obese women who have a preponderance of abdominal subcutaneous fat (apple-shaped) have a higher risk of developing insulin resistance, diabetes and CVD relative to women who carry their excess weight in gluteal/thigh adipose tissue (pear-shaped). This proposal addresses the fundamental mechanisms associated with depot specific adipose function directly in humans. Our preliminary published and new unpublished studies support the hypothesis that fat depot specific gene expression and associated epigenetic signatures are maintained when abdominal vs. gluteal pre-adipocytes are cultured in vitro. The proposed new experiments will extend these studies to reveal genome-wide differences in epigenetic marks in adipose tissue and adipocytes from both men and women. We will also investigate the different gene expression patterns and associated epigenetic marks that define the pear vs. apple body type of the American adult female. We will uncover new fundamental molecular signatures and processes that are relevant to development of insulin resistance, diabetes and cardiovascular disease.